In the last year, we have completed three projects designed to elucidate the genetic pathogenesis of ALS: In the first project, we sought to identify causative variants for ALS by conducting a genome-wide association study in a cohort of 432 Irish individuals. The relatively homogeneous genetic background of this island population enhances its power to detect relevant loci. Following replication in our previously published North American dataset, the strongest association was a variant in the gene encoding DPP6, a component of type A neuronal transmembrane potassium channels.[unreadable] In the second project, we screened the TARDBP gene for mutations in a cohort of 279 sporadic ALS cases and 806 neurologically normal control individuals. Mutations in the TARDBP gene have been recently described in families with ALS, but the importance of the gene in the pathogenesis of the commoner sporadic form of the disease was unknown. No mutations or pathogenic structural variants were found in the ALS cases suggesting that this particular gene is not a common cause of sporadic motor neuron degeneration. [unreadable] In the third project, we undertook a two-stage genome-wide association study to identify the genes involved in ALS: we followed our initial genome-wide association study of 545,066 SNPs in 553 individuals with ALS and 2,338 controls of European descent by testing the 7,600 most associated SNPs from the first stage in three independent cohorts consisting of 2,160 cases and 3,008 controls. Two adjacent SNPs on chromosome 7p13.3, rs2708909 and rs2708851, were significantly associated with disease in the combined joint analysis (P-value = 5.47x10-7 and 7.22x10-7). The most associated SNP, rs2708909, is located in intron 3 of SUNC1, which encodes a nuclear envelope protein known to interact with microtubules and dynein. Our findings suggest that SUNC1 variants contribute to susceptibility to sporadic ALS. [unreadable] In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of ALS using both candidate gene approaches and genome-wide association methods. Each of the three studies employed large cohorts of research subjects, and utilized the Illumina genotyping platform and the sequencing facilities available within the Laboratory of Neurogenetics, NIA.